At the population level, malaria remains an intractable problem in Malawi, a small but ecologically diverse country in southeastern Africa. The reasons for malaria's intransigence are enigmatic, but new findings emerging from our current ICEMR investigations have provided some clues: ? Plasmodium parasite infection prevalence is greater in school-age children than in under-five year olds ? School-age children are also most likely to carry gametocytes, the stage infectious to Anopheles vectors ? Molecular (q-PCR) diagnostic tests revealed low-level infection in people who were asymptomatic, hence not being treated (hidden reservoirs), hence a likely source of undetected transmission ? Anopheles vector abundance varied across a 20-km radius around a major urban center, with hot spots being linked to micro-environmental heterogeneity, and not to a simple urban-rural designation ? Prevention failures may result from insecticide resistance and patterns of insecticide treated net use. At the individual level, only a small proportion of people infected with Plasmodium parasites ever experience symptoms of malaria illness; most co-exist asymptomatically with the parasite. An even smaller proportion evolves into severe and complicated malaria, but the mortality rates are high. The mechanisms underlying progression along the infection-to-disease spectrum are not known, in part because reliably identifying individuals at the infection extremes (persistently asymptomatic and life-threatening cerebral malaria) has only recently become feasible. The Malawi ICEMR team has the capacity to sustain long-term observations of human cohorts in different transmission settings and to collect extensive ecological, entomological and parasitological data to evaluate: ? patterns of pathogen transmission and human host responses, ? effectiveness of multiple interventions against transmission and infection in different environments, ? relationships between infection frequency/duration and disease severity, ? impacts of insecticide resistance and insecticide treated net (ITN) quality and use on disease patterns, ? contributions of parasite growth rate, clonality, pro- and anti-inflammatory host responses ? importance of ?holes? in the immune response to variant surface antigens to disease progression. Over the course of seven years of research, which will span Malawi's next large national ITN distribution program, the Malawi ICEMR will identify why malaria control efforts in Malawi have been ineffective thus far, and will provide data-driven suggestions regarding approaches that are more likely to be effective. Studies will be undertaken in three ecologically and epidemiologically different districts that span a range of transmission intensities. Analyses of changing transmission and disease will compare patterns before, during and after the nation-wide ITN distribution program.